Creating genetics-based infusion centers: a case study of two models

Laney, Dawn A.; White, Amy; Rhead, William J.; Fernhoff, Paul M.

doi:10.1097/gim.0b013e31818050a2

Cited by 2 publications

(1 citation statement)

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“…It requires repeated and life-long treatment and has been clinically approved for some lysosomal storage diseases without CNS involvement (6). In mouse models of MLD, intravenous injection of recombinant human ARSA showed some promising effects including improvement of the CNS histopathology and function (7,8).…”

Section: Introductionmentioning

confidence: 99%

Arylsulfatase A Overexpressing Human iPSC-derived Neural Cells Reduce CNS Sulfatide Storage in a Mouse Model of Metachromatic Leukodystrophy

et al. 2015

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Metachromatic leukodystrophy (MLD) is an inherited lysosomal storage disorder resulting from a functional deficiency of arylsulfatase A (ARSA), an enzyme that catalyzes desulfation of 3-O-sulfogalactosylceramide (sulfatide). Lack of active ARSA leads to the accumulation of sulfatide in oligodendrocytes, Schwann cells and some neurons and triggers progressive demyelination, the neuropathological hallmark of MLD. Several therapeutic approaches have been explored, including enzyme replacement, autologous hematopoietic stem cell-based gene therapy, intracerebral gene therapy or cell-based gene delivery into the central nervous system (CNS). However, long-term treatment of the blood-brain-barrier protected CNS remains challenging. Here we used MLD patient-derived induced pluripotent stem cells (iPSCs) to generate long-term self-renewing neuroepithelial stem cells and astroglial progenitors for cell-based ARSA replacement. Following transplantation of ARSA-overexpressing precursors into ARSA-deficient mice we observed a significant reduction of sulfatide storage up to a distance of 300 µm from grafted cells. Our data indicate that neural precursors generated via reprogramming from MLD patients can be engineered to ameliorate sulfatide accumulation and may thus serve as autologous cell-based vehicle for continuous ARSA supply in MLD-affected brain tissue.

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Section: Introductionmentioning

confidence: 99%